This invention is generally in the area of drug delivery systems, especially in the area of gastrointestinal, vaginal and respiratory drug delivery.
Drug delivery takes a variety of forms, depending on the agent to be delivered and the administration route. A preferred mode of administration is non-invasive; i.e., administration via nasal or oral passages. Some compounds are not suited for such administration, however, since they are degraded by conditions in the gastrointestinal tract or do not penetrate well into the blood stream.
Controlled release systems for drug delivery are often designed to administer drugs in specific areas of the body. In the gastrointestinal tract it is critical that the drug not be entrained beyond the desired site of action and eliminated before it has had a chance to exert a topical effect or to pass into the bloodstream. If a drug delivery system can be made to adhere to the lining of the appropriate viscus, its contents will be delivered to the targeted tissue as a function of proximity and duration of the contact.
There are two major aspects to the development of an adhesive bond between a polymer and the gastrointestinal tissue: (i) the surface characteristics of the bioadhesive material, and (ii) the nature of the biological material with which the polymer comes in contact. The intestinal mucosa is formed of a continuous sheet of epithelial cells of absorptive and mucin-secreting cells. Overlying the mucosa is a discontinuous protective coating, the mucus, which is made of more than 95% water, as well as electrolytes, proteins, lipids and glycoproteinsxe2x80x94the latter being responsible for the gel-like characteristics of the mucus. These glycoproteins consist of a protein core with covalently attached carbohydrate chains terminating in either sialic acid or L-fucose groups. The carbohydrate structure of the intestinal mucous glycoproteins is similar to that of the glycoproteins which are part of the epithelial cell membrane. The mucous glycoproteins act as xe2x80x9cdummy receptorsxe2x80x9d for carbohydrate binding ligands which have evolved in nature to allow microorganisms and parasites to establish themselves on the gut wall. One function of the mucus is to intercept these ligands and associated ineffective agents and thereby protect the mucosa.
An orally ingested product can adhere to either the epithelial surface or the mucus. For the delivery of bioactive substances, it would be advantageous to have a polymeric device adhere to the epithelium rather than solely to the mucous layer, although mucoadhesion may also substantially improve bioavailability. For some types of imaging purposes, adhesion to both the epithelium and mucus is desirable whereas in pathological states, such as in the case of gastric ulcers or ulcerative colitis, adhesion to cells below the mucous layer may occur.
Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells.
Several microsphere formulations have been proposed as a means for oral drug delivery. These formulations generally serve to protect the encapsulated compound and to deliver the compound into the blood stream. Enteric coated formulations have been widely used for many years to protect drugs administered orally, as well as to delay release. Other formulations designed to deliver compounds into the blood stream, as well as to protect the encapsulated drug, are formed of a hydrophobic protein, such as zein, as described in PCT/US90/06430 and PCT/US90/06433; xe2x80x9cproteinoidsxe2x80x9d, as described in U.S. Pat. No. 4,976,968 to Steiner; or synthetic polymers, as described in European Patent application 0 333 523 by The UAB Research Foundation and Southern Research Institute. EPA 0 333 523 describes microparticles of less than ten microns in diameter that contain antigens, for use in oral administration of vaccines. The microparticles are formed of polymers such as poly(lactide-co-glycolide), poly(glycolide), polyorthoesters, poly(esteramides), polyhydroxybutyric acid and polyanhydrides, and are absorbed through the Peyer""s Patches in the intestine, principally as a function of size.
It would be advantageous if there was a method or means for controlling or increasing the absorption of these particles through the mucosal lining, or for delaying still further transit of the particles through the nasal or gastrointestinal passages.
Duchene, et al., Drug Dev. Ind. Pharm. 14(2and3), 283-318 (1988), reviews the pharmaceutical and medical aspects of bioadhesive systems for drug delivery. xe2x80x9cBioadhesionxe2x80x9d is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is clearly one solution to the problem of inadequate residence time resulting from the stomach emptying and intestinal peristalsis, and from displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds must form. Bioadhesive properties of the polymers is affected by both the nature of the polymer and by the nature of the surrounding media.
Duchene, et al., tested polymers for bioadhesion by measuring the surface tension between a plate containing a mucus sample and a polymer coated glass plate. They review other systems using intestinal membrane rather than a mucosal solution, and in vivo studies using rats and radiolabeled polymeric material in a gelatin capsule. A number of polymers were characterized as to their bioadhesive properties but primarily in terms of xe2x80x9cexcellentxe2x80x9d or xe2x80x9cpoorxe2x80x9d. Polycarbophils and acrylic acid polymers were noted as having the best adhesive properties, although the highest adhesive forces were still less than 11 mN/cm2.
Others have explored the use of bioadhesive polymers. Smart, et al., J. Pharm. Pharmacol. 36:295-299 (1984), reported on a method to test adhesion to mucosa using a polymer coated glass plate contacting a dish of mucosa. A variety of polymeric materials were tested, including sodium alginate, sodium carboxymethylcellulose, gelatin, pectin, and polyvinylpyrrolidone. Gurney, et al., Biomaterials 5, 336-340 (1984), concluded that adhesion may be effected by physical or mechanical bonds; secondary chemical bonds; and/or primary, ionic or covalent bonds. Park, et al., Alternative Approaches to Oral Controlled Drug Delivery: Bioadhesives and In-Situ Systems 163-183 J. M. Anderson and S. W. Kim, ed., Recent Advances in Drug Delivery (Plenum Press NY 1984), reported on the use of fluorescent probes in cells to determine adhesiveness of polymers to mucin/epithelial surfaces. Their results indicated that anionic polymers with high charge density appear to be preferred as adhesive polymers.
None of these studies involved the study of tensile measurement between microspheres and intestinal tissue. Microspheres will be affected by other factors, such as the mucosal flow, peristaltic motion, high surface area to volume ratio, Mikos, et al., in J. Colloid Interface Sci. 143, 2:366-373 (May 1991) and Lehr, et al., J. Controlled Rel. Soc. 13:51-62 (1990), both disclose the bioadhesive properties of polymers used for drug delivery: polyanhydrides and polyacrylic acid, respectively. Mikos, et al., report that the bioadhesive forces are a function of surface area, and are significant only for particles in excess of 900 microns in diameter (having a maximum adhesive force of 120 xcexcN for a sphere with a diameter of approximately 1200xcexc, equivalent to 10.9 mN/cm2), when measured in vitro. However, they also note that this may not be an adequate adhesive force in vivo, since the larger particle size is also subjected to greater flow conditions along the mucosa which may serve to displace these larger particles. In addition, Mikos, et al., found very small forces for particles smaller than 750xcexc. Lehr, et al., screened two commercially available microparticles of a diameter in excess of 500 microns formed of copolymers of acrylic acid, using an in vitro system, and determined that one copolymer xe2x80x9cPolycarbophilxe2x80x9d increased adhesion over a control but that the other polymer did not. Polymeric coatings were also applied to polyhydroxyethylmethacrylic acid and tested in an in vivo model. As shown in Table 1 of Mikos, et al., the maximum adhesive force was approximately 9 mN/cm2 for Polycarbophil.
Most prior art techniques for measuring in vitro bioadhesion are based on tensile experiments. These techniques were mainly designed for large tablets or polymer coated onto glass plates. Only a few in vitro techniques for direct measurement of adhesion forces between individual microcapsules and intestinal tissue are known. Some publications report on a flow channel method. However, the only reported results are static measurements where the mucoadhesive force exerted on each particle was determined by placing small particles over intestinal mucosa and measuring the immersed surface area and the directional contact angles using video microscopy, as described by Mikos, et al.
Many of the currently approved drugs are delivered systemically only by injection due to low bioavailability when orally administered. It would be advantageous both from cost considerations as well as patient compliance and comfort if these drugs could be administered orally, nasally, or through the pulmonary tract, using a system increasing bioavailability.
It is therefore an object of the present invention to provide drug delivery formulation that are useful for drug delivery via the mucosal membranes.
Bioadhesive polymers in the form of, or as a coating on, microcapsules containing drugs, for therapeutic purposes, are described. Preferred drugs are those which are approved by the Food and Drug Administration but which are not sufficiently bioavailable when administered orally, nasally, or through the pulmonary tract, except when encapsulated within the bioadhesive polymeric microspheres described herein. The polymeric microspheres all have a bioadhesive force of at least 11 mN/cm2 (110 N/m2) using the tensile measuring device described herein. Techniques for the fabrication of bioadhesive microspheres, as well as a method for measuring bioadhesive forces between microspheres and mucosa, are also described. Preferred polymers are synthetic polymers, especially copolymers of fumaric acid and sebacic acid.